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CD19 B cell repopulation after ocrelizumab, alemtuzumab and cladribine: Implications for SARS-CoV-2 vaccinations in multiple sclerosis
Author links open overlay panelDavidBaker AmyMacDougall Angray S.Kang KlausSchmierer Gavin Giovannoni Ruth Dobson
Background
Ocrelizumab maintains B-cell depletion via six-monthly dosing. Whilst this controls relapsing multiple sclerosis, it also inhibits seroconversion following SARS-CoV-2 vaccination unlike that seen following alemtuzumab and cladribine treatment. Emerging reports suggest that 1–3% B-cell repopulation facilitates seroconversion after CD20-depletion.
Objective
To determine the frequency of B-cell repopulation levels during and after ocrelizumab treatment.
Methods
Relapse data, lymphocyte and CD19 B-cell numbers were obtained following requests to clinical trial data-repositories. Information was extracted from the phase II ocrelizumab extension (NCT00676715) trial and the phase III cladribine tablet (NCT00213135) and alemtuzumab (NCT00530348/NCT00548405) trials obtained clinical trial data requests
Results
Only 3–5% of people with MS exhibit 1% B-cells at 6 months after the last infusion following 3–4 cycles of ocrelizumab, compared to 50–55% at 9 months, and 85–90% at 12 months. During this time relapses occurred at consistent disease-breakthrough rates compared to people during standard therapy. In contrast most people (90–100%) exhibited more than 1% B-cells during treatment with either cladribine or alemtuzumab.
Conclusions
Most people demonstrate B cell repletion within 3 months of the last treatment of alemtuzumab and cladribine. However, few people repopulate peripheral B-cells with standard ocrelizumab dosing. Controlled studies are warranted to examine a view that delaying the dosing interval by 3–6 months may allow more people to potentially seroconvert after vaccination.
P.S. These controlled studies should have been down a long time ago
CoI: This is our paper !
Disclaimer:
Very helpful, MD. Thank you as always. Question: If B cell repopulation begins, does it typically ramp up quickly once it begins?
Yes once they start they repopulate up quickly
And what is the difference of Ofatumumab?
I do not have the data for ofatumumab. Novartis has signed up to clinical trials data request.com so it can be requested 18 months after the study but it will be a nightmare because their data comes from numerous studies.
But would be easier if Novartis publish their data otherwise I will go hunting. They have changed the goal posts as most studies including ofatamumumab report time to the lower limit normal of 40 cells per microlitre. the others use 80 microlitre. I decided against using 40 cells per microlitre for all the agents but to help the comparison I put some information in legend. In the FDA label it says “Data from RMS clinical studies indicate B-cell recoveries over the LLN in at least 50% of patients in 24 to 36 weeks post treatment discontinuation. Modeling and simulation for B-cell repletion corroborates these data, predicting median time to B-cell recovery of 40 weeks post treatment discontinuation”. It doesn’t describe what the LLN is and at 40 weeks it must be 80 cells/ul. However, the SMC at the EMA says “The median time to B-cell recovery to the lower limit of normal (LLN, defined as 40 cells/µl) or baseline value is 24.6 weeks”.
Now in the paper we put in Gibiansky E et al.Ocrelizumab in relapsing and primary progressive multiple sclerosis: Pharmacokinetic and pharmacodynamic analyses of OPERA I, OPERA II and ORATORIO. Br J Clin Pharmacol.2021; 87:2511. In this paper it says “However, repletion data from the Phase II study show that, following the final infusion of 600 mg ocrelizumab, median time to B‐cell repletion was 72 weeks (range 27–175), with LLN defined as 80 cells/μL. Sensitivity analyses of different LLN definitions showed median repletion times between 53 (LLN = 40 cell/μL, range 27–145) and 86 (LLN = 107 cells/μL, range 27–222) weeks”.
So now you can directly compare ofatumumab and ocrelizumab.
Bar-OR et al. 2018 Neurology. 90(20): e1805 ofatumumab repletion (remeber clinical dose is 20mg/month). The LLN was around 80 cells/ul
3mg/3month 30mg/3month 60mg/3month 60mg/month
Median time to repletion 334.0d(49.9 weeks) 329.0d(49 weeks) 421.0d(60.1 weeks) 428.0/(61.4 weeks)